The purpose of this application is to investigate novel functions of the low density lipoprotein (LDL) receptor gene family that go beyond its recognized role in the endocytosis of ligands and the control of triglyceride and cholesterol homeostasis. We will primarily address the cellular metabolism of two members of this evolutionarily highly conserved gene family, the very low density lipoprotein (VLDL) receptor and the LR8B, also known as apolipoprotein receptor-2. Recent findings that extracellular ligand interactions with these receptors may transmit signals to certain cell types and induce them to migrate through the surrounding tissue, a process of particular importance to the emerging roles of these genes in atherosclerosis and Alzheimer disease. Gene targeting was used to investigate the physiological functions of these genes in the mouse. The results of these preliminary experiments support the hypothesis that extracellular signals, transmitted by the VLDL receptor and LR8B, provide migratory cues to neurons during the formation of the brain. This signaling likely involves cytosolic adaptor proteins and non-receptor tyrosine kinases. To dissect and fully characterize the underlying pathway, mutations will be introduced into the cytoplasmic tails of both receptors that prevent them from interacting with the adaptor proteins, but will not affect their ability to undergo endocytosis. This will allow us to determine, whether a block of a signaling pathway or block of endocytosis of a specific ligand are responsible for the neuronal migration defect in VLDL receptor and LR8B deficient cells. We will extend these studies to search for novel adaptor proteins that interact with the cytoplasmic tails of LDL receptor gene family members in other tissues, in particular the liver and the vascular wall. There these interactions might modulate the ability of the receptors to remove lipoproteins from the circulation or affect the mechanisms that are the focus of this proposal are likely to have significant clinical implications and may provide new targets for drug design in the treatment of degenerative diseases of the brain and vascular wall.